The publications and other materials used herein to illuminate the background of the invention, and in particular, cases to provide additional details respecting the practice, are incorporated by reference.
Taxoids or taxanes are highly complex diterpenes many of which exhibit promising antineoplastic activity. The anti-cancer active compound taxol is the most frequently cited taxane derivative in the literature. This compound was several decades ago isolated from the bark of the Pacific Yew (Taxus brevifolia) (Wani M C et al., J Am Chem Soc 1971, 93, 2325). Taxol has shown high activity against many tumor cell line systems. It has shown excellent activity, particularly in the treatment of advanced ovarian cancer, either as such or in combination with other anti-cancer drugs. It has also been successful in the treatment of breast cancer, lung cancer, melanoma and several other cancers, too. (For clinical usage of taxol, see Rowinsky E et al., J Nail Cancer Inst 1990; 82:1247-1259).
The taxol molecule (1) is shown in Scheme 1. The molecule comprises a side chain attached no a complex ring system built up of the A-, B-, C and D-rings. Synthetic approaches to taxol and its derivatives have been extensively described in the literature (see for example Boa, Jenkins and Lawrence, Contemporary Organic Synthesis, 1994, 1, 47; Nicolaou K C et al., Angew Chem Int Ed Engl 1994, 33, 15). Despite extensive attempts, no successful total synthesis of taxol has been published until very recently (Nicolaou K C et al., Nature 1994, 367, 630; Holton R A et al., J Am Chem Soc 1994, 116, 1597; Holton R A et al., ibid, 1994, 116, 1599). To avoid the problem of direct extraction of taxol from the bark of yew trees, semisynthetic methods for the production of taxol have also been developed. The compound 10-deacetylbaccatin III (compound 2 in Scheme 2), which constitutes the ring system of taxol, can be derived from renewable needles and twigs of the yew tree. The introduction of the side chain into the 13-position of 10-deacetylbaccatin yields taxol or derivatives thereof.
The advent of chemotherapy based on taxol and its derivatives has, however, been hampered by shortcomings relating to their limited availability. Another disadvantage, particularly relating to taxol, is the low aqueous solubility. As a result of the low water solubility, formulations have been made that based on surfactants giving rise to adverse effects in some patients. Thus, there is a great need to develop a synthesis that could be used for the large scale production of taxol as well as for the production of more water soluble taxane derivatives.
Both of the problems concerning the limited availability of taxol as well as its low water solubility can be solved through the development of a sufficiently flexible entry into taxol and its structural analogues. The inventors of the present invention have recently initiated a program with this as a major goal (Koskinen A M P et al., J Chem Soc Chem Commun, 1994, 21).
Scheme 2 discloses the structure of the some taxanes with anti-cancer activity as well as 10-deacetylbaccatin III and baccatin III, compounds useful as starting materials in the semi-synthesis of taxol or its analogues. The structure of the side chain is responsible for the water solubility of the molecule. Compounds 5 to 8 (Scheme 2) have proved to have higher solubility in water than taxol itself. (See Nicolaou K C et al., Angew Chem Int Ed Engl 1994, 33, 15).